Nivolumab/Ipilimumab Approval in Advanced HCC Calls for Nuanced Look at Available Data

Partner | Cancer Centers | <b>Memorial Sloan Kettering Cancer Center </b>

Ghassan K. Abou-Alfa, MD, provides perspective on the accelerated approval of nivolumab and ipilimumab in advanced hepatocellular carcinoma.

Ghassan K. Abou-Alfa, MD

The armamentarium in advanced hepatocellular carcinoma (HCC) is rapidly evolving as evidenced by the recent accelerated approval of the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) in the second-line setting. While the approval signals a step in the right direction, more data are needed before the regimen can be appropriately sequenced into practice, according to Ghassan K. Abou-Alfa, MD.

On March 11, 2020, the FDA granted an accelerated approval to the combination of nivolumab and ipilimumab for the treatment of patients with HCC who have received prior therapy with sorafenib (Nexavar).1 The approval is based on data from a cohort of the phase I/II CheckMate-040 trial (NCT01658878), in which the reported benefit of the combination of nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks for 4 treatments, followed by a flat dose of nivolumab at 240 mg every 2 weeks, induced an objective response rate (ORR) of 32%, which included an 8% complete response (CR) rate and a 24% partial response (PR) rate. The median duration of response (DOR) was 17.5 months.2

In terms of safety, grade 3/4 treatment-related adverse events (TRAEs) in this arm were reported in 53% of patients. Immune-mediated adverse events (IMAEs) included grade 3/4 hepatitis in 20% of patients.

The accelerated approval is contingent on the results of the phase III CheckMate-9DW study (NCT04039607), which will evaluate the combination compared with sorafenib or lenvatinib (Lenvima) in the frontline setting.

The approval also comes 3 months after the developers of atezolizumab (Tecentriq) and bevacizumab (Avastin) submitted a supplemental biologics license application to the FDA for the frontline treatment of patients with unresectable HCC.

This adds further complexity to the current sequencing strategies of systemic therapies for advanced HCC, which is also pending the awaited results of the HIMALYA study (NCT03298451) evaluating durvalumab (Imfinzi) plus tremelimumab as first-line therapy in HCC.

“The field is moving by the minute. We barely had a chance to grasp the latest data of atezolizumab plus bevacizumab, and look where we are today. It's going to be a very dynamic field; and we are yet to see where all these positive outcome studies will take us,” said Abou-Alfa. “Currently, we don’t have enough data to tell us where the combination stands relative to other available combinations, especially with regard to atezolizumab/bevacizumab. These combinations should not be perceived as the same though. Intriguingly the anti—CTLA-4 plus anti–PD-1/PD-L1 combination stands out at the priming and activation level of the cancer-immunity cycle, yet hopefully at the right timing and dosing.”

In an interview with OncLive, Abou-Alfa, a medical oncologist at Memorial Sloan Kettering Cancer Center, provided perspective on the accelerated approval of nivolumab and ipilimumab in advanced HCC.

OncLive: Could you discuss the data from the CheckMate-040 trial that led to the accelerated approval of nivolumab and ipilimumab in advanced HCC?

Abou-Alfa: CheckMate-040 is a fascinating and complex phase II trial that evaluated nivolumab and later in combination with ipilimumab. The data from the trial led to the accelerated approval of nivolumab in the second-line setting. Sadly, CheckMate-459 study, the follow-up randomized phase III trial of nivolumab versus sorafenib, did not meet its primary end point in the frontline setting.

We also saw earth-shattering data with atezolizumab and bevacizumab at the 2019 ESMO Asia Congress last December in Singapore. These data showed a clear benefit with the combination of an anti—PD-L1 plus an anti-VEGF. Other combinations are being investigated; however, they should not be compared as of the same category.

The 3 categories of combinations are a checkpoint inhibitor plus an antiangiogenic agent; plus a TKI like lenvatinib (Lenvima); and plus another checkpoint inhibitor, namely anti—CTLA-4 at the priming and activation level of the cancer-immunity cycle.

We are very happy to see the data with the arm A combination of nivolumab and ipilimumab, with an ORR of 32% and a median DOR of 17.5 months, yet with a wide range from 4.6 months to more than 30.5 months. These numbers would be worth further exploring, thus the need to wait for the outcome of CheckMate-9DW phase III study, which will help define overall survival and progression-free survival outcome data—similar to the HIMALYA study evaluating durvalumab plus tremelimumab as first-line therapy.

What is your take on the data we have so far?

[These are] great positive, novel, and disruptive data! We're very thrilled to see added options made available to patients with HCC. However, the data still have to be dissected further. The two pending points are lining up of therapies and how much of anti—CTLA- 4 is needed, and whether dosing and timing imply a different benefit magnitude, let alone the adverse events implications as we have witnessed so far with the combination of nivolumab and ipilimumab.

Will the accelerated approval change practice?

We all are thankful and respectful of the FDA’s decision to approve the combination of nivolumab and ipilimumab. This is now an added option of therapy. We may feel intrigued and wait though to see further details plus other studies. After all, this is what the accelerated approval mechanism is all about.

How could atezolizumab/bevacizumab’s use in the frontline setting affect the use of nivolumab/ipilimumab in the second-line setting?

Where the different options would fall into place has yet to be determined. The combination of atezolizumab and bevacizumab is lining up to help as a frontline therapy. The combination of tremelimumab/durvalumab and pembrolizumab/lenvatinib might do the same. Then, the question will be where we should place sorafenib, lenvatinib, and the combination of nivolumab/ipilimumab. This concept would permit the use of the combination therapies to be followed, if needed, by the current first-line therapeutic options of lenvatinib and sorafenib; we are unlikely to discredit the positive values these drugs add and the great efforts behind their study and development. Where the combination of nivolumab and ipilimumab in the second-line setting stands is puzzling and needs further analysis and discussion. We also need to remember that nivolumab and ipilimumab will ultimately be evaluated in the frontline setting.

Could you expand on the safety profile of the combination?

There have been different therapy decisions based on the doses and frequency of ipilimumab and nivolumab, and a lot of intrigue regarding the safety of the dosing schedules. We have yet to see biologically where the timing and the amount of ipilimumab as anti—CTLA-4 needed. Is it every 6 weeks, every 3 weeks, or just 1 dose? We don’t know. This has yet to be discovered. We sure would like to see more safety data.

Is there anything else about the combination you want to emphasize?

In summary, the combination of nivolumab and ipilimumab provided good data. However, we’re a little bit perplexed by the small number of patients on the study and the different dosing and frequencies evaluated. There is a certain settling to nivolumab at 1mg/kg plus ipilimumab at 3 mg/kg every 3 weeks for 4 treatments, followed by a flat dose of nivolumab 240 mg every 2 weeks. The second-line indication is adding to the confusion, in view of the positive outcome of the phase III trial of the combination of atezolizumab/bevacizumab. It’s a good move in the right direction, but we need to analyze the data further.


  1. U.S. Food and Drug Administration approves Opdivo (nivolumab) + Yervoy (ipilimumab) for patients with hepatocellular carcinoma (HCC) previously treated with sorafenib [news release]. Princeton, NJ: Bristol-Myers Squibb; March 11, 2020. Accessed March 12, 2020.
  2. El-Khoueiry AB, Hsu C, Kang YK, et al. Safety profile of nivolumab (NIVO) plus ipilimumab (IPI) combination therapy in patients with advanced hepatocellular carcinoma (HCC) in the CheckMate 40 study. Presented at: 2019 International Liver Cancer Association Annual Conference; September 20-22, 2019; Chicago, IL. Abstract O-13.